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Journal of Diagnostic Imaging in Therapy. 2014; 1(1): 20-48

Grachev et al.

Open Medscience

Peer-Reviewed Open Access

JOURNAL OF DIAGNOSTIC IMAGING IN THERAPY
Journal homepage: www.openmedscience.com

Research Article

An in vivo Positron Emission Tomography Study of Adenosine
2A Receptor Occupancy by Preladenant using 11C-SCH442416
in Healthy Subjects
Igor D. Grachev 1,*, Miroslava Doder 2, †, David J. Brooks 2,3, Rainer Hinz4
1
2

3
4


Schering-Plough Research Institute, Kenilworth, NJ, USA
MRC Clinical Sciences Centre and Division of Neuroscience, Faculty of Medicine, Imperial
College, London, UK
Hammersmith Imanet Ltd., GE Healthcare, Hammersmith Hospital, London, UK
Wolfson Molecular Imaging Centre, University of Manchester, UK
deceased

* Author to whom correspondence should be addressed
Igor Grachev, M.D., Ph.D.
Independent R&D Pharmaceutical Consultant
O: +1 732 642 7773
grachevi@hotmail.com

Abstract:
Background: This PET study was conducted to investigate the receptor occupancy of 11CSCH442416 in the human brain and to determine plasma concentrations and dose of preladenant
which result in inhibition of 11C-SCH442416 binding to adenosine 2A receptors. Preladenant is a
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Journal of Diagnostic Imaging in Therapy. 2014; 1(1): 20-48

Grachev et al.

novel non-dopaminergic, high-affinity, and highly selective A2A receptor antagonist being investigated
for the management of Parkinson’s disease.
Methods: This was an open-label, single-center, and pharmacokinetic-pharmacodynamic study
performed in 18 healthy subjects. All subjects received an intravenous injection of the radiotracer 11CSCH442416. Thirteen subjects received a single dose of preladenant 10, 50 or 200 mg orally at 1, 6 or
12 hrs prior to radiotracer injection.
Results: A blockade of >80% was reached after 50-200 mg doses of preladenant. The Emax model
that predicted plasma concentrations corresponding to 50%, 80%, and 90% receptor occupancy was
validated. A 5 mg dose, administered BID, was estimated to provide ≥50% receptor occupancy in
approximately 75% of the population for the majority of waking hours (12 hours/day).
Conclusions: Single doses of preladenant were well-tolerated. The Cmax and AUC values of
preladenant increased in a dose-related manner. In this study we demonstrated the importance of PET
imaging for establishing PK-PD relationships and utilizing this tool in confirming proof-of-target and
dose guidance for Phase 2/3 clinical trials.
Keywords: 11C-SCH442416; adenosine A2A receptor; PET; spectral analysis

1. Introduction
Parkinson’s disease (PD) is an age-related, progressive neurodegenerative disease characterized by
abnormal gait and posture, resting tremor, loss of balance, bradykinesia, and muscular rigidity.
Comorbid alterations in mood [1] and cognition [2] are frequently in evidence in PD patients. In the
US and Western Europe, approximately 100,000 to 150,000 new cases of PD are diagnosed each year.
The disease typically begins to manifest in individuals between 50 and 60 years of age, although onset
at younger ages occurs. Current prevalence of PD is estimated at 1.5 million cases in the US and
Europe, with the number of incident cases increasing rapidly as the population ages.
The pathology of PD is characterized by a progressive degeneration of the pigmented neurons
in the substantia nigra and the presence of intracytoplasmic inclusions known as Lewy bodies. The
selective loss of the nigro-striatal dopaminergic pathway and consequent reduction in dopamine levels
of the striatum is responsible for the limb bradykinesia and rigidity associated with the disease. The
specific etiology of the disease, however, is multifactorial and a number of susceptibility genes and
monogenic causes are now known. Manifestation of symptoms is likely to involve a combination of
genetic vulnerability, accelerated aging and epigenetic stimuli such as oxidative stress, mitochondrial
dysfunction, and excitotoxicity, which ultimately cause specific deterioration of the nigro-striatal
dopaminergic pathway.
A potential approach to the treatment of PD is the use of adenosine receptor antagonists.
Preladenant is a novel non-dopaminergic, non-methylxanthine, high-affinity (Ki= 1.1 nM), and highly
selective (>1000-fold versus A1, A2B, and A3 receptors) A2A receptor antagonist being investigated for
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Journal of Diagnostic Imaging in Therapy. 2014; 1(1): 20-48

Grachev et al.

the management of movement disorders, including idiopathic Parkinson’s disease. The purine
nucleotide adenosine is a ubiquitous modulator of neuronal function in the central and peripheral
nervous systems. Adenosine has been shown to exert its biological action through a class of G-protein
coupled receptors of which four subtypes have been cloned to date: A1, A2A, A2B, and A3 [3]. Of these,
the A2A [4] receptor is highly concentrated in discrete brain nuclei of the basal ganglia (e.g., caudate
nucleus, globus pallidus, nucleus accumbens, and olfactory tubercles) [5,6]. Within the striatum A2A
receptors are predominantly localized to the GABAergic striatopallidal enkephalin-expressing neurons,
where they are co-localized with dopamine D2 receptors, and to intrastriatal GABAergic recurrent
collaterals [7,8].
Blockade of A2A receptors on both of these GABAergic neuronal pathways reduces indirect
striato-pallidal output neuron activity, thereby compensating for the overactivity of these cells due to
dopamine deficiency in PD [9]. The net result is reduced inhibition of neuronal activity in the thalamus
(GABAergic) and the thalamo-cortical (glutamatergic) feedback loop [10,11]. These manifests as a
suppression of inappropriate motor behaviors characteristic of PD: bradykinesia and akinesia.
Numerous functional studies support the hypothesis that blockade of striatal A2A receptors may
provide relief of PD symptoms. A2A antagonists have been shown to activate dopaminergic pathways
and to reverse motor impairment in rodent models of PD [12-14]. In nonhuman primates with basal
ganglia lesions, A2A receptor antagonists significantly improve motor function without causing
dyskinesia [15-17]. Moreover, since the consequence of A2A blockade does not depend on an intact
nigro-striatal dopaminergic pathway, it is anticipated that this strategy may provide an opportunity to
significantly delay the onset of dopaminergic therapy.
11
C-SCH442416, the radiotracer being used in this PET study, is a potent, high affinity
(Ki=0.048 nM) that is selective for the A2A receptor. It has greater than 20,000 fold selectivity for A2A
over A1, A2B, and A3 receptors. It has been previously shown that this radiotracer exhibits robust
specific binding and signal-to-noise ratios and is not significantly metabolised in the brain of
nonhuman primates [18-20]. It is anticipated that data from this study will confirm that preladenant
induces behavioral changes associated with its occupancy of A2A receptors.
The
objectives
of
the
present
open-label,
single-center,
pharmacokinetic
(PK)/pharmacodynamic (PD), and adaptive study were to investigate the receptor occupancy of 11CSCH442416 in the human brain and to determine the plasma concentration and dose of preladenant
which results in inhibition of 11C-SCH442416 binding to A2A receptors.

2. Materials and Methods
2.1. Study design and subjects
This was an open-label, single-center, single-dose, PK/PD, and adaptive design PET study performed
in 18 healthy male subjects between the ages of 25 and 50 years (mean=32.5±7.7 years), body weight
between 62.8 kg and 103.3 kg (mean = 79.52±11.84 kg), and Body Mass Index ranging from 19.2 to
29.0 kg/m2 (mean = 24.66±2.81 kg/m2) were enrolled into and completed this study.

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Grachev et al.

Inclusion and exclusion criteria were chosen to ensure that a well-defined healthy subject population
was included in the study. This included detailed medical history and complete physical examination,
laboratory test results within normal range, normal vital signs, and normal or clinically acceptable 12lead electrocardiogram (ECG). Exclusion criteria included any history or presence of clinically
significant local or systemic infectious disease within 4 weeks prior to study drug administration, any
significant medical disorder which would have required a physician’s care, any history of seizures or
autoimmune disorders, any history of mental instability; blood donation within 3 months before
administration; history or presence of drug abuse; smoking more than 10 cigarettes or equivalent /day;
subjects who have received radiation exposure (including x-rays) within 12 calendar months prior to
the study; subjects with significant anatomical abnormalities noted on the MRI of the brain or any
condition which would preclude MRI examination (e.g., implanted metal, severe claustrophobia);
individuals who had evidence of only one patent arterial supply to the hand (Allen Test).
An initial cohort of five subjects (Baseline Cohort 1) was administered 11C-SCH442416 with the
injected activity ranged from 349 to 381 MBq. Data for one subject could not be used because of an
acquisition failure during the PET scan; thus data for four subjects were used as baseline [21]. The
next cohort of two subjects (Cohort 2) received preladenant 200 mg orally under fasting conditions 12
hours before the administration of 11C-SCH442416. The following cohort of three subjects (Cohort 3)
received preladenant 200 mg 1 hour before the administration of 11C-SCH442416. The next three
cohorts, Cohorts 4, 5, and 6, with two subjects each, received preladenant 200 mg, 50 mg, and 10 mg,
respectively, all at 6 hours before the administration of 11C-SCH442416. Two subjects were included
in Cohort 7; both received preladenant 10 mg, one at 1 hour before the administration of 11CSCH442416 and the other at 12 hours before the administration of 11C-SCH442416. The PET scan for
1 subject given 200 mg treatment in Cohort 3 was not performed because radiotracer specific activity
was below specification. Therefore, PET analysis included 16 subjects (4 baseline subjects with
radiotracer alone and 12 subjects treated with various doses of preladenant). Because of estimated
radiation exposures, subjects were dosed only once with 11C-SCH442416.
The first dose level was 200 mg or the maximum tolerated dose from the single rising dose
study and was chosen to set an upper limit on receptor occupancy. Each of the subsequent lower doses
(50 and 10 mg) in the progressive decrease was administered at 1, 6 or 12 hours prior to 11CSCH442416 PET after the receptor occupancy data of the previously administered higher dose were
evaluated. The decision to progress to lower dose levels at different scanning times was determined by
review of the PET images and time-activity curves of 11C-SCH442416 activity in the putamen,
caudate, thalamus and cerebellum.
Blood PK samples for preladenant plasma concentration assessment were collected pre dose (0
hour), 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, and 24 hours after dosing of preladenant.
Additionally, samples were drawn immediately before the PET scan and at the end of the 90-minute
PET study. This information was used to characterize the effect of preladenant on the receptor
occupancy profile at 1, 6, or 12 hours post dose. Plasma samples were analyzed using a validated
liquid chromatographic method with tandem mass spectrometric detection.

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Grachev et al.

This study was conducted in accordance with the Declaration of Helsinki Principles, ICH guidelines
for Good Clinical Practice and after approval was obtained from the Research Ethics Committees at
Central Middlesex and Hammersmith Hospitals, London; and the U.K. Administration of Radioactive
Substances Advisory Committee. All subjects signed and dated an IEC-approved consent form before
being enrolled into the study. All subjects were covered by Health Insurance System and/or in
compliance with the recommendations of National Law in force relating to biomedical research.
2.2. PET/MRI scanning protocol
All PET scans were performed on the high-sensitivity Siemens/CTI scanner ECAT EXACT3D with an
axial field of view of 23.4 cm and 95 reconstructed transaxial image planes [22]. A 5-minute
transmission scan using a 137Cs point source was carried out prior to each study for subsequent
attenuation and scatter correction. The 95-minute three-dimensional dynamic emission scan was
acquired in list mode. In the post acquisition frame rebinning, 28 time frames of increasing length were
generated (30-second background frame prior to the injection, one 15-second frame, one 5-second
frame, four 10-second frames, four 60-second frames, and seventeen 300-second frames). The PET
images were reconstructed using filtered back projection based on the following set of parameters:
scatter correction was model based; attenuation correction was measured and segmented;
reconstruction machine was SUN CPU with a zoom 2.5; spatial resolution of reconstructed images was
5.1 mm x 5.1 mm x 5.9 mm; and reconstructed voxel size was 2.10 mm x 2.10 mm x 2.43 mm.
The radiotracer 11C-SCH442416 synthesis was described previously [19] and was injected into
an antecubital vein as a smooth bolus over 30 seconds. The mean injected radioactivity dose of 11CSCH442416 was 362±9 MBq, radiochemical purity of the injected radiotracer at time dispense was >
99%, injected mass of SCH442416 was 2.54±1.1 µg, and specific activity at time of injection was
66.6±31.0 MBq/nmol. The estimated volume for injected radiotracer was 1.91±0.78 mL, and pH of the
injected solution was 5.62±0.42.
After i.v. injection of 11C-SCH442416, the radioactivity in blood was measured using a
continuous on-line radioactivity detector system [23]. Discrete arterial blood samples were withdrawn
before the PET scan (baseline sample) and throughout the PET scans via a cannula inserted into the
opposite arm to which the radiotracer was administered. The withdrawal times were to be 5, 10, 15,
20, 30, 40, 50, 60, 75, and 95 minutes post 11C-SCH442416 injection for the first three scans.
Beginning with the fourth scan, this sampling schedule was subsequently revised to more frequent
sampling at the beginning due to the fast kinetics of 11C-SCH442416.
For each subject, brain MRIs were acquired with T1 weighted RF spoiled gradient echo volume
scans on a 1 Tesla Philips Medical Systems HPQ+ Scanner. The echo time TE was 6 ms, the repetition
time TR was 21 ms, the flip angle was 35, yielding an image resolution of 1.6 mm x 1.6 mm x 1.0 mm
(AP, LR, and HF, respectively).
A set of 49 volumes of interest (VOI), which included the cerebellum, was defined with the
help of a probabilistic brain atlas template [24].
The standard MRI on which the VOI template had been defined was normalized to the individual MRI
using the SPM99 software package (Statistical Parametric Mapping, Wellcome Department of
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Journal of Diagnostic Imaging in Therapy. 2014; 1(1): 20-48

Grachev et al.

Cognitive Neurology, London, United Kingdom). The calculated image transformation parameters
were then applied to transform the VOI template, resulting in a map of VOIs of the subject’s individual
MRI space. The individual MRI was then coregistered to the PET image summed from 1 to 30 minutes
after tracer injection using an automated multiresolution optimization procedure [25]. On the
individual MRI, the following six ROIs were defined manually: left and right putamen, left and right
caudate, and left and right thalamus. The cerebellum was defined with the help of a probabilistic brain
atlas template [24]. For the manual drawing of the ROIs as well as for the generation of the TACs, the
medical imaging software package ANALYZE [26,27] was used.
2.3. Primary endpoint and statistical methods
2.3.1. Quantification of radiotracer binding and receptor occupancy
Spectral analysis was used to estimate the regional binding potentials and receptor occupancies. The
use of spectral analysis for the quantification of dynamic PET studies was introduced by Cunningham
and Jones [28]. In contrast to compartmental modeling, spectral analysis does not define a certain
structure of compartments. Spectral analysis is used in PET for the quantification of cerebral glucose
metabolism in 18F-FDG studies, for the quantification of cerebral blood flow in scans with 15O-water
and for the quantification of neuroreceptor binding, e.g. in studies with the opiate receptor radiotracer
11
C-diprenorphine [28]. For a general discussion of the applicability of spectral analysis see the work
of Schmidt [29]. For the analysis of the dynamic PET scans with 11C-SCH442416, spectral analysis
was used because of its ability to separate three components of the tissue response function:
irreversible components = slow nondisplaceable uptake, reversible components = fast nonspecific and
specific (displaceable) binding, and fast components = plasma volume. Only the specific binding in
blocked scans (reversible components) turned out to be displaceable by the blocking drug. The
irreversible uptake did not seem to be affected by the blocker. BP estimates were calculated as
VDtarget/VDreference – 1, VDtarget being the volume of distribution of the reversible components in the
target region and VDreference the volume of distribution of the reversible nonspecific binding in the
cerebellum.
The mean OCC of a region for each subject was calculated as:

 BP

OCC  1  Blocked  100%,
 BPBaseline 
with BP blocked as the binding potential of the subject after administration of blocking compound
preladenant, and BP baseline as the mean baseline binding potential in that region.

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Journal of Diagnostic Imaging in Therapy. 2014; 1(1): 20-48

Grachev et al.

2.3.2. Pharmacokinetic analysis
Individual plasma concentration-time data were analyzed using model-independent methods [30]. The
maximum concentration (Cmax, ng/mL), time of maximum concentration (Tmax, hr), and the time of
final quantifiable sample (tf, hr) were the observed values. The area under the plasma concentrationtime curve from time 0 to tf (AUC [tf], ng∙hr/mL) was calculated using the linear trapezoidal method.
The terminal phase rate constant (K, hr-1) was calculated as the negative of the slope of the terminal
log-linear portion of the plasma concentration-time curve using linear regression. The area under the
plasma concentration-time curve from Time 0 to infinity (AUC [I], ng∙hr/mL) was calculated as
follows:
Cest
AUC(I) = AUC (tf) 
K
where Cest is the estimated plasma concentration at tf.
The apparent terminal-phase half-life (t½, hr) was calculated as follows:
t½ =

ln(2)
K

These data are listed in Table 2 and Table 3. PK results were summarized using geometric mean and
coefficient of variation for each dose level. Preladenant plasma concentration values were used for PKPD analyses.
2.3.3. Pharmacokinetic-pharmacodynamic (PK-PD) analysis
Receptor occupancy data from the putamen region of the brain were selected for PK-PD model
development due to the high binding potential for A2A receptors and less variation between the
unilateral (left and right regional) occupancy values of preladenant in this region of interest (ROI),
which is involved in pathophysiology of Parkinson’s disease. Relationship between plasma
preladenant concentrations obtained at the start of PET image acquisition and the receptor occupancy
in the specific ROI (i.e., putamen) was graphically explored. An Emax model[31] described below
was selected to fit the PK-PD data.
E C
E  max
EC 50  C
where,
E=

Receptor occupancy (%)

C=

Plasma concentration (ng/mL) corresponding to the receptor occupancy E

Emax=

An asymptote representing the maximum receptor occupancy (%)

EC50=

Plasma concentration (ng/mL) corresponding to 50% of Emax

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Journal of Diagnostic Imaging in Therapy. 2014; 1(1): 20-48

Grachev et al.

Two additional parameters were derived to characterize various levels of receptor occupancy of
preladenant:
EC80=

Plasma concentration (ng/mL) corresponding to 80% of Emax. The EC80 was
calculated directly from eq.1 by substituting E=80% of Emax, and then solving
for C.

ECopt=

Plasma concentration (ng/mL) corresponding to optimal receptor occupancy.
ECopt was defined as the lowest observed plasma concentration that achieved the
model estimated Emax (i.e., ≥ 85% occupancy).

In order to obtain population estimates of the duration of receptor occupancy, the available plasma
concentration data from five completed Phase 1 studies (n=130) were pooled. Descriptive statistics,
such as the10th and 25th percentile, mean, and maximum plasma concentration values were calculated
at each time point. Population estimates of receptor occupancy durations were estimated as explained
by a specific case below. Following a single oral dose of 25 mg of preladenant, the time duration over
which the 10th percentile plasma concentration remained greater than or comparable to the EC50 value,
was considered as the population estimate of time duration for 50% receptor occupancy of preladenant
in 90% of population. In this manner, prelandenant receptor occupancy durations were determined
following various doses and QD or BID regimens of preladenant in ~75% and ~90% of population.

3. Results and Discussion
3.1. Summed PET images and time activity curves
A total of 18 healthy subjects completed the study: 13 received oral preladenant before 11C-SCH
442416 PET (Cohorts 2-6) while 5 had 11C-SCH442416 PET alone (Cohort 1). The tracer injected
activity ranged from 349 to 381 MBq. Data for one baseline subject were not usable because of an
acquisition failure during the PET scan. The PET scan for one subject from the preladenant treatment
group had to be canceled, because the radiotracer delivered was below specifications, and thus only 12
subjects were included in the blockade results (Table 1).

Subject No.

Brain
side

Binding Potential
Putamen

Caudate

Receptor Occupancy

Thalamus

Putamen

Caudate

Thalamus

0.26
0.32
0.91
1.57
0.23
0.27
0.44
0.24
0.53
0.48

----------

----------

----------

Baseline Cohort No. 1
1
2
4
5

left
right
left
right
left
right
left
right

average
SD

2.85
2.94
2.52
3.82
2.53
2.39
1.12
1.54
2.47
0.84

1.72
1.33
2.21
2.95
1.21
1.45
0.98
0.86
1.59
0.70

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Journal of Diagnostic Imaging in Therapy. 2014; 1(1): 20-48
Subject No.

Brain
side

Grachev et al.

Binding Potential
Putamen

Caudate

Receptor Occupancy

Thalamus

Putamen

Caudate

Thalamus

0.22
0.14
0.43
0.42
0.30
0.15

57%
47%
57%
62%
56%
6.29

53%
60%
58%
62%
58%
3.86

58%
73%
19%
21%
43%
27.0

0.05
0.16
0.38
0.23
0.21
0.14

94%
89%
84%
84%
88%
4.79

116%
100%
94%
111%
105%
10.0

91%
69%
27%
56%
61%
26.7

0.03
0.18
0.48
0.52
0.30
0.24

91%
83%
72%
80%
82%
7.85

108%
109%
78%
77%
93%
17.9

95%
66%
9%
1%
43%
45.3

0.14
0.10
0.04
0.08
0.09
0.04

86%
91%
78%
79%
84%
6.14

101%
115%
74%
75%
91%
20.2

74%
80%
93%
85%
83%
8.04

0.50
0.18
0.79
0.78
0.56
0.29

51%
66%
54%
40%
53%
10.7

63%
23%
49%
51%
47%
16.8

5%
67%
-49%
-47%
-6%
54.7

0.54
0.44
0.49
0.07

77%
73%
75%
2.83

69%
86%
78%
12.0

-1%
16%
8%
12.0

0.34
0.50
0.42
0.11

18%
20%
19%
1.41

-9%
39%
15%
33.9

36%
6%
21%
21.2

200 mg/12 hr Cohort No. 2
6
7

left
right
left
right

average
SD

1.05
1.31
1.07
0.94
1.09
0.16

0.74
0.64
0.67
0.60
0.66
0.06

200 mg/1 hr Cohort No. 3
8
9

left
right
left
right

average
SD

0.16
0.28
0.38
0.40
0.30
0.11

-0.25
0.00
0.10
-0.18
-0.08
0.16

200 mg/6 hr Cohort No. 4
10
11

left
right
left
right

average
SD

0.23
0.41
0.69
0.49
0.45
0.19

-0.12
-0.14
0.35
0.36
0.11
0.28

50 mg/6 hr Cohort No. 5
12
13

left
right
left
right

average
SD

0.33
0.23
0.53
0.51
0.40
0.14

-0.02
-0.24
0.41
0.40
0.14
0.32

10 mg/6 hr Cohort No. 6
14
15

left
right
left
right

average
SD

1.22
0.83
1.14
1.47
1.17
0.26

0.60
1.22
0.81
0.78
0.85
0.26

10 mg/1 hr Cohort No. 7
16

left
right

average
SD

0.57
0.66
0.61
0.06

0.50
0.23
0.36
0.19

10 mg/12 hr Cohort No. 7
17

left
right

average
SD

2.03
1.97
2.00
0.04

1.73
0.98
1.36
0.53

Note: Subject No. 3 had equipment error during PET data acquisition, data can not be recovered. Subject No.12 had
enlarged ventricles (right > left), which can explain the unusually high occupancy value for the right caudate. Shown
average and standard deviation (SD) values.

ISSN: 2057-3782 (Online)
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28


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